G-protein coupled receptor 40 (GPR40) and G-protein coupled receptor (GPR120) are expressed on intestinal L cells, monocytes and/or macrophages. We investigated the effect of GW9508 (GW), a GPR40 and GPR120 dual agonist, on modulating autoimmunity in NOD mice. New-onset diabetic NOD mice were treated with GW for up to 8 weeks. Nonfasting blood glucose was monitored. After the treatment, CD4+CD25+FoxP3+ T (Treg) cells in thymus, spleen and pancreatic lymph nodes were measured. To detect IL-17+CD4+ T (Th17) cells, lymphocytes from these mice were cultured for 5 days. To determine in vitro effect of GW on Th17 cells, lymphocytes from NOD mice were cultured with or without GW. Cytokines and chemokines in supernatants were determined. Diabetes was reversed in 13% of vehicle (DMSO) treated mice, in 54% of mice treated with GW at 10mg/kg/day and in 69% of mice treated with GW at 20 mg/kg/day (P<0.01). The insulitis score was significantly lower in GW-treated mice (P<0.05). Although the percentage of Treg cells was not significant different, the percentage of Th17 cells and the ratio of Th17 cells to Treg cells in GW-treated mice were significantly lower (P<0.01). Th17 cells in GW-treated lymphocytes in culture were significantly reduced (P<0.05). IL-17, IFN-γ, IP-10, RANTES, and MIP-1α in supernatants of GW-treated lymphocytes were also significantly reduced (P<0.05). Our data indicate that targeting GPR40 /GPR120 is a new therapeutic approach for treating type 1 diabetes.
- Copyright © 2013 by The American Association of Immunologists, Inc.